Subject(s)
Colonic Neoplasms , Colorectal Neoplasms, Hereditary Nonpolyposis , Heart Atria , Female , Humans , Male , Middle Aged , Adenocarcinoma/complications , Adenocarcinoma/pathology , Colonic Neoplasms/complications , Colonic Neoplasms/pathology , Colorectal Neoplasms, Hereditary Nonpolyposis/complications , Heart Atria/diagnostic imaging , Heart Atria/pathology , Heart Neoplasms/complications , Heart Neoplasms/diagnostic imagingABSTRACT
BACKGROUND: Lynch syndrome (LS) is one of the most common hereditary cancer syndromes worldwide. Dominantly inherited mutation in one of four DNA mismatch repair genes combined with somatic events leads to mismatch repair deficiency and microsatellite instability (MSI) in tumours. Due to a high lifetime risk of cancer, regular surveillance plays a key role in cancer prevention; yet the observation of frequent interval cancers points to insufficient cancer prevention by colonoscopy-based methods alone. This study aimed to identify precancerous functional changes in colonic mucosa that could facilitate the monitoring and prevention of cancer development in LS. METHODS: The study material comprised colon biopsy specimens (n = 71) collected during colonoscopy examinations from LS carriers (tumour-free, or diagnosed with adenoma, or diagnosed with carcinoma) and a control group, which included sporadic cases without LS or neoplasia. The majority (80%) of LS carriers had an inherited genetic MLH1 mutation. The remaining 20% included MSH2 mutation carriers (13%) and MSH6 mutation carriers (7%). The transcriptomes were first analysed with RNA-sequencing and followed up with Gorilla Ontology analysis and Reactome Knowledgebase and Ingenuity Pathway Analyses to detect functional changes that might be associated with the initiation of the neoplastic process in LS individuals. FINDINGS: With pathway and gene ontology analyses combined with measurement of mitotic perimeters from colonic mucosa and tumours, we found an increased tendency to chromosomal instability (CIN), already present in macroscopically normal LS mucosa. Our results suggest that CIN is an earlier aberration than MSI and may be the initial cancer driving aberration, whereas MSI accelerates tumour formation. Furthermore, our results suggest that MLH1 deficiency plays a significant role in the development of CIN. INTERPRETATION: The results validate our previous findings from mice and highlight early mitotic abnormalities as an important contributor and precancerous marker of colorectal tumourigenesis in LS. FUNDING: This work was supported by grants from the Jane and Aatos Erkko Foundation, the Academy of Finland (330606 and 331284), Cancer Foundation Finland sr, and the Sigrid Jusélius Foundation. Open access is funded by Helsinki University Library.
Subject(s)
Colorectal Neoplasms, Hereditary Nonpolyposis , Microsatellite Instability , Mitosis , Humans , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/pathology , Colorectal Neoplasms, Hereditary Nonpolyposis/complications , Female , Male , Mitosis/genetics , Middle Aged , Mutation , Adult , Aged , MutL Protein Homolog 1/genetics , Gene Expression Profiling , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Colorectal Neoplasms/etiology , Carcinogenesis/genetics , DNA Mismatch Repair/genetics , TranscriptomeSubject(s)
Carcinoma, Squamous Cell , Colorectal Neoplasms, Hereditary Nonpolyposis , Skin Neoplasms , Humans , Colorectal Neoplasms, Hereditary Nonpolyposis/pathology , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/complications , Skin Neoplasms/pathology , Skin Neoplasms/diagnosis , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/diagnosis , Female , Male , Middle Aged , Asian People , China , Adult , East Asian PeopleABSTRACT
Lynch syndrome-associated endometrial cancer patients often present multiple synchronous tumors and this assessment can affect treatment strategies. We present a case of a 27-year-old woman with tumors in the uterine corpus, cervix, and ovaries who was diagnosed with endometrial cancer and exhibited cervical invasion and ovarian metastasis. Her family history suggested Lynch syndrome, and genetic testing identified a variant of uncertain significance, MLH1 p.L582H. We conducted immunohistochemical staining, microsatellite instability analysis, and Sanger sequencing for Lynch syndrome-associated cancers in three generations of the family and identified consistent MLH1 loss. Whole-exome sequencing for the corpus, cervical, and ovarian tumors of the proband identified a copy-neutral loss of heterozygosity (LOH) occurring at the MLH1 position in all tumors. This indicated that the germline variant and the copy-neutral LOH led to biallelic loss of MLH1 and was the cause of cancer initiation. All tumors shared a portion of somatic mutations with high mutant allele frequencies, suggesting a common clonal origin. There were no mutations shared only between the cervix and ovary samples. The profiles of mutant allele frequencies shared between the corpus and cervix or ovary indicated that two different subclones originating from the corpus independently metastasized to the cervix or ovary. Additionally, all tumors presented unique mutations in endometrial cancer-associated genes such as ARID1A and PIK3CA. In conclusion, we demonstrated clonal origin and genomic diversity in a Lynch syndrome-associated endometrial cancer, suggesting the importance of evaluating multiple sites in Lynch syndrome patients with synchronous tumors.
Subject(s)
Colorectal Neoplasms, Hereditary Nonpolyposis , Endometrial Neoplasms , MutL Protein Homolog 1 , Neoplasms, Multiple Primary , Adult , Female , Humans , Colorectal Neoplasms, Hereditary Nonpolyposis/complications , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , DNA Mismatch Repair , Endometrial Neoplasms/genetics , Endometrial Neoplasms/pathology , Genomics , Microsatellite Instability , MutL Protein Homolog 1/genetics , Neoplasms, Multiple Primary/geneticsABSTRACT
A 44-year-old woman with Lynch syndrome was referred to our hospital for treatment of recurrence of microsatellite instability-high rectal cancer. [18F]Fluorodeoxyglucose (18FDG)-positron emission tomography revealed a peritoneal metastasis with invasion to the small intestine and left ureter. The peritoneal metastasis was diagnosed initially as unresectable because of extensive invasion to the left ureter requiring nephrectomy. Hence, first-line treatment with pembrolizumab was started. After the first course of pembrolizumab, she developed hydronephrosis and a resulting urinary tract infection (UTI). A percutaneous nephrostomy was performed to control the UTI. After six courses of pembrolizumab, 18FDG-positron emission tomography showed that the peritoneal metastasis was smaller with significantly reduced 18FDG uptake, and it was then diagnosed as resectable without nephrectomy. She underwent R0 resection of the peritoneal metastasis with partial resection of the small intestine. Intraoperatively, the peritoneal metastasis showed no invasion of the left ureter, allowing its preservation. The percutaneous nephrostomy was removed postoperatively, and she has not developed any subsequent UTIs. Histopathologically, the tumor showed a pathological complete response to pembrolizumab. To the best of our knowledge, this is the first case of conversion therapy with pembrolizumab for peritoneal metastasis with hydronephrosis.
Subject(s)
Antibodies, Monoclonal, Humanized , Colorectal Neoplasms, Hereditary Nonpolyposis , Hydronephrosis , Peritoneal Neoplasms , Rectal Neoplasms , Humans , Hydronephrosis/etiology , Female , Adult , Peritoneal Neoplasms/secondary , Peritoneal Neoplasms/drug therapy , Peritoneal Neoplasms/complications , Rectal Neoplasms/pathology , Rectal Neoplasms/complications , Rectal Neoplasms/drug therapy , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/adverse effects , Colorectal Neoplasms, Hereditary Nonpolyposis/complications , Antineoplastic Agents, Immunological/therapeutic use , Urinary Tract Infections/drug therapy , Nephrostomy, PercutaneousSubject(s)
Colorectal Neoplasms, Hereditary Nonpolyposis , Colorectal Neoplasms , Prostatic Neoplasms , Male , Humans , Colorectal Neoplasms, Hereditary Nonpolyposis/complications , Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis , Prostatic Neoplasms/complications , Prostatic Neoplasms/diagnosisSubject(s)
Colorectal Neoplasms, Hereditary Nonpolyposis , Endoscopic Mucosal Resection , Neoplasms, Second Primary , Stomach Neoplasms , Humans , Colorectal Neoplasms, Hereditary Nonpolyposis/complications , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/surgery , Gastric Mucosa/surgery , MutS Homolog 2 Protein/genetics , Neoplasms, Second Primary/surgery , Retrospective Studies , Stomach Neoplasms/complications , Stomach Neoplasms/surgeryABSTRACT
Metastatic and localized mismatch repair-deficient (dMMR) tumors are exquisitely sensitive to immune checkpoint blockade (ICB). The ability of ICB to prevent dMMR malignant or pre-malignant neoplasia development in patients with Lynch syndrome (LS) is unknown. Of 172 cancer-affected patients with LS who had received ≥1 ICB cycles, 21 (12%) developed subsequent malignancies after ICB exposure, 91% (29/32) of which were dMMR, with median time to development of 21 months (interquartile range, 6-38). Twenty-four of 61 (39%) ICB-treated patients who subsequently underwent surveillance colonoscopy had premalignant polyps. Within matched pre-ICB and post-ICB follow-up periods, the overall rate of tumor development was unchanged; however, on subgroup analysis, a decreased incidence of post-ICB visceral tumors was observed. These data suggest that ICB treatment of LS-associated tumors does not eliminate risk of new neoplasia development, and LS-specific surveillance strategies should continue. These data have implications for immunopreventative strategies and provide insight into the immunobiology of dMMR tumors.
Subject(s)
Colorectal Neoplasms, Hereditary Nonpolyposis , Colorectal Neoplasms , Humans , Colorectal Neoplasms, Hereditary Nonpolyposis/complications , Colorectal Neoplasms, Hereditary Nonpolyposis/drug therapy , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Immune Checkpoint Inhibitors , Colorectal Neoplasms/pathologyABSTRACT
BACKGROUND: Extensive colectomy (subtotal or total colectomy) is often advised for carriers of Lynch syndrome with colorectal cancer. However, the risk of metachronous colorectal cancer might differ by Lynch syndrome variant, meaning that partial colectomy, which has better functional outcomes, might be adequate for some patients with low-risk variants. We aimed to assess the risk of metachronous colorectal cancer after partial colectomy and extensive colectomy in carriers of Lynch syndrome with different pathogenic variants. METHODS: For this retrospective cohort study, carriers of Lynch syndrome with colorectal cancer in the Netherlands were identified by linkage of the Dutch Foundation for the Detection of Hereditary Tumors (StOET) database and the Dutch Nationwide Network and Registry of Histopathology and Cytopathology (PALGA) database. Data on demographics, Lynch syndrome variants, colorectal cancers, surgery types, mortality, and surveillance colonoscopies were extracted. Data on colorectal cancer and surveillance colonoscopies were updated until Feb 28, 2022. Data on survival status was updated until Feb 7, 2022. MLH1, MSH2, and EPCAM were classified as high-risk variants and MSH6 and PMS2 as low-risk variants. Patients for whom the type of surgery was unknown were excluded. Cox regression time-to-event analyses were done to assess the risk of metachronous colorectal cancer in four subgroups based on pathogenic variant (high-risk vs low-risk variants) and the extent of surgery (extensive colectomy vs partial colectomy). Sex, age at the time of primary colorectal cancer, primary colorectal cancer stage, performance of surveillance colonoscopies, adherence to the surveillance guidelines, and time period of primary colorectal cancer diagnosis were added to the model as possible confounders. Metachronous colorectal cancer was defined as colorectal cancer diagnosed more than 6 months after the primary colorectal cancer. Patients were censored at time of death or assembly of the database. FINDINGS: Of 1908 carriers of Lynch syndrome registered in StOET, 532 with a history of colorectal cancer were identified after linkage with PALGA. Five carriers were excluded because of an unknown surgery type, leaving 527 in our sample (mean age at primary colorectal cancer 48·7 years [SD 12·1]; 274 [52%] male and 253 [48%] female). 121 (23%) patients developed metachronous colorectal cancer (median time from primary colorectal cancer to metachronous colorectal cancer 11·0 years [IQR 2·1-17·8]). Metachronous colorectal cancer occurred in 12 (12%) of 97 patients with high-risk variants and extensive colectomy, in 85 (32%) of 267 patients with high-risk variants and partial colectomy, in zero (0%) of 11 patients with low-risk variants and extensive colectomy, and in 24 (16%) of 152 patients with low-risk variants and partial colectomy. Partial colectomy was associated with a higher risk of metachronous colorectal cancer than extensive colectomy in the high-risk variant group (hazard ratio 1·97, 95% CI 1·04-3·73; p=0·039). The risk of metachronous colorectal cancer did not differ between carriers of low-risk variants who had partial colectomy and those of high-risk variants who had extensive colectomy (1·14, 0·55-2·36; p=0·72). INTERPRETATION: The risk of metachronous colorectal cancer after partial colectomy in carriers of low-risk variants is similar to the risk after extensive colectomy in carriers of high-risk variants. This finding suggests that partial colectomy followed by endoscopic surveillance is an appropriate management approach to treat colorectal cancer in carriers of low-risk Lynch syndrome variants. FUNDING: None.
Subject(s)
Colorectal Neoplasms, Hereditary Nonpolyposis , Humans , Male , Female , Middle Aged , Colorectal Neoplasms, Hereditary Nonpolyposis/complications , Colorectal Neoplasms, Hereditary Nonpolyposis/epidemiology , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Retrospective Studies , Netherlands/epidemiology , Colectomy , RiskABSTRACT
BACKGROUND: We evaluated the risk of metachronous colorectal cancer (mCRC) and explored the optimal extent of colectomy in patients with Lynch syndrome (LS) and first colon cancer (fCC) in Japan, where the extent of colectomy for colon cancer (CC) is shorter than that in Western countries. METHODS: The clinicopathologic and survival data of patients with LS who developed CC were collected from a nationwide database and analyzed retrospectively. The cumulative incidence of mCRC after actual segmental colectomy was compared with that of mCRC when more extensive colectomy was assumed. RESULTS: There were 142 eligible patients (65 female). The median age at fCC surgery was 46.5 (range: 14-80) years. The cumulative incidence of 5-, 10-, and 20-year mCRC rate was 13.4%, 20.8%, and 53.6%, respectively. The incidence was higher in the left-sided group (splenic flexure to rectosigmoid colon, n = 54) than in the right-sided group (cecum to transvers colon, n = 88) (66.3% vs. 45.3% in 20 years, P < 0.01). Assuming that all patients would have undergone hemicolectomy or total colectomy, the estimated mCRC risk was 41.5% and 9.4% (P < 0.01, vs. actual procedures), respectively. The 20-year overall survival rate of all the patients was 83.3% without difference by fCC sidedness (P = 0.38). CONCLUSIONS: To reduce the incidence of mCRC, patients with genetically diagnosed LS and fCC, preferentially located in the left-sided colon, may need to undergo more extended colectomy than that usually performed in Japan. However, such extended colectomy should be counterbalanced with favorable overall survival and actual risk of mCRC development.
Subject(s)
Colonic Neoplasms , Colorectal Neoplasms, Hereditary Nonpolyposis , Neoplasms, Second Primary , Adolescent , Adult , Aged , Aged, 80 and over , Female , Humans , Middle Aged , Young Adult , Colectomy/adverse effects , Colectomy/methods , Colonic Neoplasms/surgery , Colorectal Neoplasms, Hereditary Nonpolyposis/complications , Colorectal Neoplasms, Hereditary Nonpolyposis/surgery , Colorectal Neoplasms, Hereditary Nonpolyposis/pathology , Japan/epidemiology , Neoplasms, Second Primary/pathology , Retrospective Studies , MaleABSTRACT
RATIONALE: Lynch syndrome is caused by germline mutations of DNA mismatch repair genes. A significant risk increase for several types of cancer is one of the characteristics of lynch syndrome. PATIENT CONCERNS: A 45-year-old female presented to the emergency department with abdominal pain that had persisted for a month. DIAGNOSES: The abdominal and pelvic computed tomography scan showed edematous and thickening of the proximal small bowel wall, as well as dilatation of the proximal bowel and stomach. INTERVENTIONS: Tumor resection of the small bowel was performed, and adenocarcinoma was confirmed pathologically. Microsatellite instability was also confirmed. OUTCOMES: Postoperative imaging revealed soft tissue lesions with potential for tumor seeding. Two months after the first surgery, a secondary surgery was performed as a result of cancer recurrence. The patient received chemotherapy with capecitabine. The latest computed tomography scan, performed 19 months after the cessation of chemotherapy, did not show any recurrence. LESSONS: In the rare incidence of small bowel cancer genetic mutation testing and detailed family history should be actively considered.
Subject(s)
Adenocarcinoma , Colorectal Neoplasms, Hereditary Nonpolyposis , Duodenal Neoplasms , Female , Humans , Middle Aged , Colorectal Neoplasms, Hereditary Nonpolyposis/complications , Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Neoplasm Recurrence, Local/pathology , Adenocarcinoma/complications , Adenocarcinoma/genetics , Adenocarcinoma/pathology , Intestine, Small/surgery , Intestine, Small/pathology , Mutation , Microsatellite Instability , Duodenal Neoplasms/pathology , DNA Mismatch RepairABSTRACT
Lynch syndrome (LS) markedly increases risks of colorectal and endometrial cancers. Early detection biomarkers for LS cancers could reduce the needs for invasive screening and surgical prophylaxis.To validate a panel of methylated DNA markers (MDM) previously identified in sporadic colorectal cancer and endometrial cancer for discrimination of these cancers in LS.In a case-control design, previously identified MDMs for the detection of colorectal cancer and endometrial cancer were assayed by qMSP on tissue-extracted DNA. Results were normalized to ACTB values within each sample. Least absolute shrinkage and selection operator models to classify colorectal cancer and endometrial cancer were trained on sporadic cases and controls and then applied to classify colorectal cancer and endometrial cancer, in those with LS, and cross-validated.We identified colorectal cancer cases (23 with LS, 48 sporadic), colorectal controls (32 LS, 48 sporadic), endometrial cancer cases (30 LS, 48 sporadic), and endometrial controls (29 LS, 37 sporadic). A 3-MDM panel (LASS4, LRRC4, and PPP2R5C) classified LS-CRC from LS controls with an AUC of 0.92 (0.84-0.99); results were similar for sporadic colorectal cancer. A 6-MDM panel (SFMBT2, MPZ, CYTH2, DIDO1, chr10.4479, and EMX2OS) discriminated LS-EC from LS controls with an AUC of 0.92 (0.83-1.0); the AUC for sporadic endometrial cancer versus sporadic controls was nominally higher, 0.99 (0.96-1.0).MDMs previously identified in sporadic endometrial cancer and colorectal cancer discriminate between endometrial cancer and benign endometrium and colorectal cancer and benign colorectum in LS. This supports the inclusion of patients with LS within future prospective clinical trials evaluating endometrial cancer and colorectal cancer MDMs and may provide a new avenue for cancer screening or surveillance in this high-risk population. PREVENTION RELEVANCE: Lynch syndrome (LS) markedly increases risks of colorectal and endometrial cancers. Early detection biomarkers for LS cancers could reduce the needs for invasive screening and surgery. Methylated DNA markers previously identified in sporadic endometrial cancer and colorectal cancer discriminate between benign and cancer tissue in LS.
Subject(s)
Colorectal Neoplasms, Hereditary Nonpolyposis , Endometrial Neoplasms , Female , Humans , Colorectal Neoplasms, Hereditary Nonpolyposis/complications , Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Genetic Markers , Endometrial Neoplasms/diagnosis , Endometrial Neoplasms/genetics , Risk Factors , Endometrium , Microsatellite InstabilityABSTRACT
Lynch syndrome (LS) is an autosomal dominant genetic disorder defined by germline mutations in one of four mismatch repair genes including PMS2, MLH2, MSH1, MSH2, or deletion in the EPCAM gene.1 The most common urologic manifestation of LS is upper tract urothelial carcinoma, which occurs in up to 20% of patients with LS.2 While data are scarce, there is growing evidence of an increased relative risk of bladder malignancy in patients with LS.3,4 Bladder tumors in children are a rare entity and the link between pediatric bladder tumors and LS has not been previously reported to our knowledge.
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Carcinoma, Transitional Cell , Colorectal Neoplasms, Hereditary Nonpolyposis , Urinary Bladder Neoplasms , Male , Humans , Child , Urinary Bladder Neoplasms/complications , Urinary Bladder Neoplasms/diagnosis , Urinary Bladder Neoplasms/genetics , Carcinoma, Transitional Cell/complications , Carcinoma, Transitional Cell/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/complications , Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Urinary Bladder , DNA Mismatch RepairABSTRACT
Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer (HNPCC) occurs due to microsatellite instability (MSI) caused by mutations in one of the mismatch repair genes leading to deficient mismatch repair proteins (dMMR). Although lung cancer is very common there is no established association between LS and lung cancer. In this manuscript we describe a case of lung cancer in a LS patient and then summarize available literature on this topic. Sixty seven y/o female patient with history of stage I colon and urothelial cancer, meeting the Amsterdam criteria, was diagnosed with LS on genetic testing. Sixteen years after the diagnosis of colon cancer, she was found to have adenocarcinoma of the lung with Next-generation sequencing (NGS) testing revealing the presence of germline mutation in MSH2 in the tumor cells indicating the possibility of LS driven lung cancer. However, subsequent immunohistochemistry (IHC) on tumor cells indicated proficient mismatch repair genes confirming the sporadic nature of lung cancer. On review of literature, we found that the coincidental presence of lung cancer in patients with LS can sometimes be mistaken for causation and may lead to confusion. Lynch syndrome associated tumors which are microsatellite instable (MSI) can be treated effectively with immunotherapy with durable responses, however, not all tumors in patient with LS are MSI impacting the choice of therapy.
Subject(s)
Colorectal Neoplasms, Hereditary Nonpolyposis , Lung Neoplasms , Female , Humans , Colorectal Neoplasms, Hereditary Nonpolyposis/complications , Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Genetic Predisposition to Disease , Genetic Testing , Germ-Line Mutation , Lung Neoplasms/complications , Lung Neoplasms/genetics , Microsatellite Instability , Mutation , AgedABSTRACT
OBJECTIVE: We aimed to elucidate the pathogenesis of ovarian cancer through the loss of mismatch repair (MMR) proteins in women with Lynch syndrome (LS) in this report. CASE REPORT: Two women with LS underwent surgery for synchronous endometrial cancer and ovarian cancer. In both cases, immunohistochemical examination showed concomitant MMR protein deficiency in endometrial cancer, ovarian cancer, and contiguous ovarian endometriosis. In Case 1, the macroscopically normal ovary included multiple endometrioses with MSH2 and MSH6 expression, and FIGO grade 1 endometrioid carcinoma and contiguous endometriosis without MSH2 and MSH6 expression. In Case 2, all endometriotic cells contiguous with carcinoma in the lumen of the ovarian cyst showed loss of the expression of MSH2 and MSH6. CONCLUSION: Ovarian endometriosis with MMR protein deficiency may progress to endometriosis-associated ovarian cancer in women with LS. Diagnosing endometriosis in women with LS during surveillance is important.
Subject(s)
Carcinoma, Endometrioid , Colorectal Neoplasms, Hereditary Nonpolyposis , Endometrial Neoplasms , Endometriosis , Ovarian Neoplasms , Protein Deficiency , Female , Humans , Endometriosis/complications , Colorectal Neoplasms, Hereditary Nonpolyposis/complications , Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis , Colorectal Neoplasms, Hereditary Nonpolyposis/pathology , DNA Mismatch Repair , MutS Homolog 2 Protein/genetics , MutS Homolog 2 Protein/metabolism , Ovarian Neoplasms/pathology , Carcinoma, Endometrioid/complications , Carcinoma, Endometrioid/pathology , Endometrial Neoplasms/complications , Endometrial Neoplasms/pathology , DNA-Binding Proteins/geneticsSubject(s)
Appendiceal Neoplasms , Colorectal Neoplasms, Hereditary Nonpolyposis , Endometrial Neoplasms , Humans , Female , Colorectal Neoplasms, Hereditary Nonpolyposis/complications , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Appendiceal Neoplasms/complications , Appendiceal Neoplasms/geneticsSubject(s)
Appendiceal Neoplasms , Colorectal Neoplasms, Hereditary Nonpolyposis , Endometrial Neoplasms , Humans , Female , Colorectal Neoplasms, Hereditary Nonpolyposis/complications , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Appendiceal Neoplasms/complications , Appendiceal Neoplasms/geneticsSubject(s)
Colorectal Neoplasms, Hereditary Nonpolyposis , Hair Diseases , Pilomatrixoma , Skin Neoplasms , Female , Humans , Colorectal Neoplasms, Hereditary Nonpolyposis/complications , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , DNA Mismatch Repair/genetics , Pilomatrixoma/complications , Pilomatrixoma/genetics , Hair Diseases/complications , Hair Diseases/genetics , Skin Neoplasms/complications , Skin Neoplasms/geneticsABSTRACT
Hereditary gastrointestinal cancer is associated with molecular and neoplastic precursors which have revealed much about sporadic carcinogenesis. Therefore, an appreciation of constitutional and somatic events linked to these syndromes have provided a useful model for the development of risk models and preventative strategies. In this review, we focus of two of the best characterized syndromes, Lynch syndrome (LS) and familial adenomatous polyposis (FAP). Our understanding of the neoplasia-immune interaction in LS has contributed to the development of immune mediated therapies including cancer preventing vaccines and immunotherapy for cancer precursors. Chemoprevention in LS with aspirin and nonsteroidal anti-inflammatory drugs has also translated into clinical cancer, however the efficacy of such agents in FAP remains elusive when cancer is applied as an endpoint in trials rather than the use of 'indirect' endpoints such as polyp burden, and requires further elucidation of biological mechanisms in FAP. Finally, we review controversies in gastrointestinal surveillance for LS and FAP, including limitations and opportunities of upper and lower gastrointestinal endoscopy in the prevention and early detection of cancer.